Rehabilitation, as well as quality of life, in Veterans with nerve and spinal cord injury, traumatic limb amputation, burn injury, and peripheral neuropathy is severely hampered by chronic pain and spasticity. Current treatments in many cases are ineffective or partially effective, and can be addictive. Our Center has developed robust research programs with unique capabilities to develop novel, more effective, and non-addictive treatments for Veterans with chronic pain and spasticity. Our research has progressed from molecular physiological studies in vitro and in animal models, to stem cell-derived models such as iPSCs and clinical translational studies, and from rare human familial disorders that provide genetic models to more common disorders that affect broader populations. We will now build on this progress in the five major research programs summarized below. Research Program I: Nav1.7?From Target to Therapy for Pain. We have provided a direct link between Nav1.7 and human pain disorders, and collaborated with Pfizer and Biogen to advance clinical studies of orally-bioavailable, Nav1.7-selective blockers for the treatment of neuropathic pain. As a parallel route to new pain medications, we will also move forward with a large-scale in-house effort to identify the atomic structure of human Nav1.7 and the molecular determinants of the dual Nav1.7 blocking/gating modifying action of carbamazepine, which should provide a high-resolution scaffold for rational drug design. Research Program II: Molecular Genetics of Pain Resilience. We are a worldwide hub for molecular genetic studies on IEM, a genetic model of human neuropathic pain, in which gain-of-function mutations of Nav1.7 produce profound hyperexcitability of peripheral pain-signaling DRG neurons that cause pain. We now plan in-depth study of a family with the Nav1.7-S241T mutation that causes IEM, whose individual members each manifest pain with distinctly different severity, using an innovative platform of iPSC-derived sensory neurons, and next-generation sequencing to identify and validate allelic variants that confer pain resilience. Research Program III: Additional Targets for Pain Pharmacotherapy. Our studies have identified and validated Nav1.8 and Nav1.9 as additional targets for pain in humans, and have expanded the spectrum of human neuropathic pain disorders associated with mutations in Na+ channels. We will extend our findings of a dual action of CBZ as a Na+ channel blocker/gating modifier, from Nav1.7 to Nav1.8 to establish the generalizability of this novel concept. We will build a proteomics platform to identify channel partners that regulate trafficking of Nav1.9 within nociceptors, which will advance us toward screening platforms and enhance understanding of this channel, which has been implicated in both somatic and visceral pain. Research Program IV: Neuroprotective Strategies in Sodium-Channel Related Peripheral Neuropathies. We have started to unravel the cellular pathways that contribute to axonal degeneration in peripheral neuropathies, and have shown that Na+ channel blockers and inhibitors of Na+/Ca2+ exchanger can rescue degenerating axons in vitro. We will use in vitro functional assays, and in vivo transgenic animal models, to advance our understanding of the mechanisms by which Nav1.7 channel variants associated with painful peripheral neuropathy lead to degeneration of axons of DRG neurons, and will assess treatment strategies with the goal of implementing them in clinical translational studies. Research Program V: Advancing Toward Translational Studies in SCI. Our Center has provided substantial evidence for!a strong correlation between dendritic spine dysgenesis and hyperexcitability disorders associated with SCI, and for a role of sodium channels, especially in astrocytes, in the formation of glial scars. We will target the Rac1-Pak1 pathway, which we have implicated in dendritic spine dysgenesis, and also investigate mechanisms that inhibit axonal regeneration, including factors within the glial scar, with the goal of developing more effective strategies for repair and protection of the injured CNS.